Amide derivatives as 5-HT1A ligands

ABSTRACT

Amide Derivatives of formula (I) wherein R 1  is a mono or bicyclic heteroaryl radical, R 2  is cycloalkyl, R 3  and R 4  each represent hydrogen or lower alkyl, and R 5  is a group of formula (A) or (B) or (C): R 8  --CH 2  --CH 2  -- or (D) or (E): R 9  OCH 2  CHOHCH 2  -- or (F): R 9  OCH 2  CH 2  -- and their pharmaceutically acceptable salts are 5-HT 1A  binding agents and may be used, for example, as anxiolytics. ##STR1##

This application is a 371 of PCT/61394/00455 filed Mar. 9, 1994.

This application is a 371 of PCT/61394/00455 filed Mar. 9, 1994.

This invention relates to novel amide derivatives, to processes fortheir preparation, to their use and to pharmaceutical compositionscontaining them. The novel compounds act on the central nervous systemby binding to 5-HT receptors (as more fully explained below) and hencecan be used as medicaments for treating humans and other mammals.

The novel compounds of the invention are those of general formula (I)##STR2## and the pharmaceutically acceptable salts thereof.

In formula (I)

R¹ is a mono or bicyclic heteroaryl radical,

R² is cycloalkyl,

R³, R^(3') and R⁴ each represent hydrogen or lower alkyl,

and R⁵ is a group of formula ##STR3## where X is --(CH₂)_(n) --, --OCH₂-- or --SCH₂ --, m is 0 or 1, n is 1, 2 or 3 and p is 0 or 1 such that(m+p) is 1 and that (m+n) is 1, 2 or 3,

R⁶ is hydrogen, lower alkyl, lower alkoxy, hydroxy, halogen,trifluoromethyl, (lower)alkoxycarbonyl, carboxamido, nitro, cyano,amino, (lower)alkylamino, di(lower)alkylamino or (lower) alkylcarbonyl,

R^(6') is hydrogen or halogen when X is --(CH₂)_(n) -- and R^(6') ishydrogen when X is --OCH₂ -- or --SCH₂ --,

R⁷ is hydrogen or lower alkyl or ##STR4## where Y is --O--, --S-- or--CH₂ --, Z represents a heteroaromatic ring fused on to thenon-aromatic ring containing the Y group

and R⁶ is as defined above and one or more R⁶ groups may be attached tothe heteroaromatic ring and/or the non-aromatic ring or

    R.sup.8 --CH.sub.2 CH.sub.2 --                             (C)

where R⁸ is a monocyclic or bicyclic heteroaryl group or ##STR5## whereR⁶ is as defined above and the indicated 7, 8 positions may optionallybe fused with a heteroaromatic ring or a further aromatic ring or

    R.sup.9 OCH.sub.2 CHOHCH.sub.2 --                          (E)

where R⁹ is a mono or bicyclic aryl or bicyclic heteroaryl group or

    R.sup.9 OCH.sub.2 CH.sub.2 --                              (F)

where R⁹ is as defined above.

The term "lower" as used herein means that the radical referred tocontains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl.

Examples of cycloalkyl groups are groups containing 3 to 8 carbon atomse.g. cyclopentyl, cyclohexyl and cycloheptyl.

When used herein "aryl" means an aromatic radical having 6 to 12 carbonatoms (e.g. phenyl or naphthyl) which optionally may be substituted byone or more substituents. Preferred substituents are lower alkyl, loweralkoxy (e.g. methoxy, ethoxy, propoxy, butoxy), halogen (e.g. chlorine),halo(lower)alkyl (e.g. trifluoromethyl), nitro, nitrile, amido,(lower)alkoxycarbonyl, amino, (lower)alkylamino and di(lower)alkylamino.

The term "heteroaryl" refers to an aromatic radical containing one ormore (e.g. 1, 2 or 3) hetero ring atoms (e.g. oxygen, nitrogen, sulphur)and which may be optionally substituted by one or more substituents.Examples of suitable substituents are given above in connection with"aryl" radicals. The heteroaryl radical may, for example, contain 5 to10 ring atom. Unless specified otherwise the heteroaryl radical ispreferably mono- or bicyclic. A monocyclic radical may, for example,contain 5 to 7 ring atoms. Preferably the hetero ring contains anitrogen atom with or without one or more further hetero atoms. Examplesof heteroaryl groups include, for example, pyridinyl, pyfimidinyl,pyrazinyl, quinolinyl, isoquinolinyl and indolyl each of which may beoptionally substituted as mentioned above.

When a "heteroaromatic ring" is fused on to a non-aromatic ring (as informula B) or is fused on to an aromatic ring (as in formula D) the"heteroaromatic ring" may be a fused "heteroaryl" group where heteroarylis defined above.

Examples of the preferred meanings of the various substituents informula (I) are given below:

R¹ is pyfidinyl, particularly 2-pyridinyl,

R² is cyelohexyl,

R³ is hydrogen and R^(3') is hydrogen or lower alkyl (e.g. methyl),

R⁴ is preferably hydrogen, methyl or propyl,

A is preferably a group of formula: ##STR6## where R⁶ is as definedabove, particularly lower alkoxy, B is preferably a group of formula:##STR7## where R⁶ is as defined above, C is preferably a group offormula ##STR8## where R⁶ is as defined above, particularly loweralkoxy, D is preferably a group of formula ##STR9## E is preferably agroup of formula ##STR10## where R⁶ is as defined above, F is preferablya group of formula ##STR11## The compounds of the invention may beprepared by methods known in the art from known starting materials orstarting materials that may be prepared by conventional methods.

One method of preparing the compounds of the invention comprises thereductive amination of a compound of formula

    R.sup.5 NHR.sup.4                                          (II)

(where R⁵ and R⁴ are as defined above) with an aldehyde of formula##STR12## (where R¹, R², R³ and R^(3') are as defined above) eg byreacting the compounds of formula (II) and (III) in the presence of areducing agent (e.g. a hydride reducing agent such as sodiumtriacetoxyborohydride) or reacting the compounds of formula (II) and(III) together followed by reduction, eg using catalytic hydrogenation.

A second method of preparing the compounds of the invention comprisesacylating an amine of formula

    R.sup.5 NR.sup.4 CH.sub.2 CR.sup.3 R.sup.3' NHR.sup.1      (IV)

(where R¹, R³, R^(3'), R⁴ and R⁵ are as defined above) with an acid offormula

    R.sup.2 COOH                                               (V)

where R² is as defined above or with an acylating derivative thereof.Examples of acylating derivatives include the acid halides (e.g.chlorides) azides, arthydrides, imidazolides (e.g. obtained fromcarbonyldiimidazole), activated esters or O-acyl ureas obtained from acarbodiimide such as a dialkylcarbodiimide particularlycyclohexyl-carbodiimide. In the compound of formula (IV) R⁴ ispreferably lower alkyl. If it is desired to prepare a compound of theinvention in which R⁴ is hydrogen it may be necessary to use a compoundof formula (IV) in which R⁴ is an amine protecting group and to removethe protecting group after the acylation reaction.

The starting compounds of formula (IV) may be prepared by reductiveamination of a compound of formula (II) above with an aldehyde offormula ##STR13## where R¹, R³, R^(3') are as defined above and R¹⁰ ishydrogen or, preferably, an amino protecting group (e.g. an urethanesuch as tert-butyloxycarbonyl), in presence of a reducing agent (e.g. ahydride reducing agent such as sodium triacetoxyborohydride) followed bydeprotection of the amino group. When R¹⁰ is, for example,tert-butyloxycarbonyl the protecting group may be removed by treatmentwith trifluoracetic acid or dilute hydrochloric acid.

A third method of preparing the compounds of the invention comprisesalkylating an amide of formula ##STR14## (where R¹ and R² are as definedabove) with an alkylating agent providing the group

    R.sup.5 NR.sup.4 CH.sub.2 CR.sup.3 R.sup.3' --

The alkylating agent may be, for example a compound of formula

    R.sup.5 NR.sup.4 CH.sub.2 CR.sup.3 R.sup.3' Q              (VIII)

(where R³, R^(3'), R⁴ and R⁵ are as defined above and Q is a leavinggroup such as a halogen (e.g. bromine) or an ester (e.g. a tosylate ortrifluoromethylsulphonate). In this process R⁴ is preferably loweralkyl.

A fourth method of preparing the compounds of the invention comprisesheteroarylating a compound of formula

    R.sup.5 NR.sup.4 CH.sub.2 CR.sup.3 R.sup.3' NHCOR.sup.2    (IX)

(where R², R³, R^(3'), R⁴ and R⁵ are as defined above) with a compoundproviding the heteroaryl group R¹.For example the reaction can becarried out with a fluoro compound of formula R¹ F in the presence of astrong non-nucleophilic base (e.g. lithium diisopropylamide). When R¹=2-pyridyl or R¹ =4 pyridyl, the reaction is preferably carried out witha 2-fluoro- or 4- fluoropyridine-N-oxide followed by deoxygenation ofthe product pyridine-N-oxide with a reducing agent such as phosphorustrichloride.

If in any of the other processes mentioned herein, a substituent on thegroup R⁵ is other than the one required the substituent may be convertedto the desired substituent by known methods. A substituent on R⁵ mayalso need protecting against the conditions under which the reaction iscarried out. In such a case the protecting group may be removed afterthe reaction has been completed.

The processes described above may be carried out to give a compound ofthe invention in the form of a free base or as an acid addition salt. Ifthe compound of the invention is obtained as an acid addition salt, thefree base can be obtained by basifying a solution of the acid additionsalt. Conversely, if the product of the process is a free base an acidaddition salt, particularly a pharmaceutically acceptable acid additionsalt, may be obtained by dissolving the free base in a suitable organicsolvent and treating the solution with an acid, in accordance withconventional procedures for preparing acid addition salts from basecompounds.

Examples of acid addition salts are those formed from inorganic andorganic acids, such as sulphufic, hydrochloric, hydrobromic, phosphoric,tartaric, fumaric, maleic, citric, acetic, formic, methanesulphonic,p-toluenesulphonic, oxalic and succinic acids.

The compounds of the invention contain one or more asymmetric carbonatoms, so that the compounds can exist in different steroisomefic forms.The compounds can be for example, racemates or optically active forms.The optically active forms can be obtained by resolution of theracemates or by asymmetric synthesis.

The compounds of the present invention possess pharmacological activity.In particular, they act on the central nervous system by binding to 5-HTreceptors. The compounds particularly bind to receptors of the 5-HT_(1A)type. The compounds of the invention can be used for the treatment ofCNS disorders, such as anxiety in mammals, particularly humans. They mayalso be used as antidepressants, antipsychotics, hypotensives and asagents for regulating the sleep/wake cycle, feeding behaviour and/orsexual function and for treating cognition disorders.

The compounds of the invention are tested for 5-HT_(1A) receptor bindingactivity in rat hippocampal membrane homogenate by the method of B SAlexander and M D Wood, J Pharm Pharmacol, 1988, 40, 888-891.

The compounds are tested for 5-HT_(1A) receptor antagonism activity in atest involving the antagonism of 5-carboxamidotryptamine in theguinea-pig ileum in vitro (based upon the procedure of Fozard et al. BrJ Pharmac, 1985, 86, 601P).

The invention also provides a pharmaceutical composition comprising acompound of formula I or a pharmaceutically acceptable acid additionsalt thereof in association with a pharmaceutically acceptable carrier.Any suitable carrier known in the an can be used to prepare thepharmaceutical composition. In such a composition, the carrier isgenerally a solid or liquid or a mixture of a solid or liquid.

Solid form compositions include powders, granules, tablets, capsules(e.g. hard and soft gelatine capsules), suppositories and pessaries. Asolid carrier can be, for example, one or more substances which may alsoact as flavouring agents, lubricants, solubilisers, suspending agents,fillers, glidants, compression aids, binders or tablet-disintegratingagents; it can also be an encapsulating material. In powders the carrieris a finely divided solid which is in admixture with the finely dividedactive ingredient. In tablets the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99%, e.g. from 0.03 to 99%. preferably1 to 80% of the active ingredient. Suitable solid carriers include, forexample, calcium phosphate, magnesium stearate, talc, sugars, lactose,dextrin, starch, gelatin, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ionexchange resins.

The term "composition" is intended to include the formulation of anactive ingredient with encapsulating material as carrier to give acapsule in which the active ingredient (with or without other carriers)is surrounded by the carrier, which is thus in association with it.Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions,emulsions, syrups, elixirs and pressufised compositions. The activeingredient, for example, can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both or pharmaceutically acceptable oils or fats.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilisers, emulsifiers, buffers, preservatives, sweetners,flavouring agents, suspending agents, thickening agents, colours,viscosity regulators, stabilisers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above. e.g. cellulose derivatives,preferably sodium carboxymethyl cellulose solution, alcohols, e.g.glyeerol and glycols) and their derivatives, and oils (e.g. fractionatedcoconut oil and arachis oil). For parenteral administration the carriercan also be an oily ester such as ethyl oleate and isopropyl myristate.Sterile liquid carriers are used in sterile liquid form compositions forparenteral administration.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. When the compound is orally active it can beadministered orally either in liquid or solid composition form.

Preferably the pharmaceutical composition is in unit dosage form e.g. astablets or capsules. In such form, the composition is sub-divided inunit dose containing appropriate quantities of the active ingredient;the unit dosage forms can be packaged composition, for example packetedpowders, vials, ampoules, prefilled syringes or sachets containingliquid. The unit dosage form can be, for example, a capsule or tabletitself, or it can be the appropriate number of any such compostions inpackage form. The quantity of the active ingredient in unit dose ofcomposition may be varied or adjusted from 0.5 mg or less to 750 mg ormore, according to the particular need and the activity of the activeingredient.

The following Examples illustrate the invention:

EXAMPLE 1N-(3-(N'-(1,2,3,4-Tetrahydro-8-methoxynaphth-2-yl)methylamino)-2-propyl)N-(2-pyridinyl)cyclohexanecarboxamide

A stirred suspension of potassium hydride, 35 wt. % suspension inmineral oil (0.01 mol) in dimethylformarnide (DMF) (100 ml) is treateddropwise under argon withN-(3-(N'-(1,2,3,4-tetrahydro-8-methoxynaphth-2-yl)methylamino)-2-propyl)N-(2-pyridinyl)amine (0.01 mol) in DMF (100 ml), after 1 h treateddropwise with cyclohexanecarbonyl chloride (0.01 mol), after 1 h treateddropwise with water (500 ml), acidified with 2N-HCl, washed with hexane(3×300 ml), basified with 2N-NaOH, and extracted with ethyl acetate(3×300 ml). The extracts are washed with brine (500 ml), dried (Na₂SO₄), and evaporated in vacuo. The residue is purified by chromatography[silica; ethyl acetate--ethanol (200:1 )] to give the product as acolourless solid.

EXAMPLE 2N-(3-(N'-(5,6,7,8-Tetrahydroquinolin-7-yl)methylamino)-2-propyl)N-(2-pyridinyl)cyclohexanecarboxamide

This compound is prepared using the procedure of Example 1 withN-(3-(N'-(5,6,7,8-tetrahydroquinolin7-yl)methylamino)-2-propyl)-N-(2-pyridinyl)amine in place of the aminereagent.

EXAMPLE 3 N-(3-(N'-(2-(3-(5-Methoxyindolyl)ethyl))methylamino)-2-propyl)N-(2-pyridinyl)cyclohexanecarboxamide

This compound is prepared using the procedure of Example 1 withN-(3-(N'-(2-(3-(5-methoxyindolyl)ethyl))methylamino)-2-propyl)-N-(2-pyridinyl)amine in place of the aminereagent.

EXAMPLE 4N-(3-(2-(2,3-Dihydro-1,4-benzodioxinyl)methylamino)-2-propyl)-N(2-pyridinyl)cyclohexanecarboxamide

A solution of 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine (0.01 mol) andN-(1-(1-formyl) ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide (0.011mol)in 1,2-dichloroethane (50 ml) is treated with sodiumtriacetoxyborohydride (0.005 mol) under argon. Acetic acid (0.01 mol isadded and the mixture stirred for 18 h, washed with water (2×50 ml),dilute aqueous sodium carbonate (50 ml), and water (50 ml), dried(MgSO₄), and evaporated in vacuo. The residue is purified bychromatography. (alumina; ethyl acetate--methanol) to give the product.

EXAMPLE 5N-(4-Aza-6-hydroxy-7-(1-naphthyloxyl)-2-heptyl)-N-(2-pyridinyl)cyclohexanecarboxamide

This compound is prepared using the procedure of Example 4 with2-hydroxy-3-(1-naphthyloxy) 1-propylamine in place of the aminecomponent.

EXAMPLE 6 N-(4-Aza-6-(1-naphthyloxy)-4-propyl-2-hexyl)-N-(2-pyridinyl)cyclohexanecarboxamide

This compound was prepared following the procedure of Example 1 withN-(4-aza-6-(1-naphthyloxy) 4-propyl-2-hexyl)pyridine-2-amine instead ofthe amine reagent.

EXAMPLE 7N-(2-(N'-(2-(2,3-Dihydro-1,4-benzodioxinyl)methyl)methylamino)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide

A mixture ofN-(2-(N'-(2-(2,3-dihydro-1,4-benzodioxinyl)methyl)-methylamino)ethyl)pyridine-2-amine(2.20 g, 7.35 mmol), cyclohexanecarbonyl chloride (1.08 g, 7.35 mmol),4-(dimethylamino)pyridine (catalytic mount) and diisopropylethylamine(0.95 g, 7.35 mmol) in dichloromethane (30 ml) was stirred over theweekend. The reaction mixture was diluted with dichloromethane (30 ml),washed with water (30 ml), dried (Na₂ SO₄) and concentrated underreduced pressure to afford an oil. The crude oil was chromatographed onalumina, eluting with ethyl acetate:hexane (1:1 to 3:1) to give an oil(1.22 g). A sample of the oil (0.50 g) was dissolved in diisopropyletherand acidified with ethereal hydrogen chloride to afford thehydrochloride salt of the title compound as an off-white solid (0.39 g)mp=83.5°-88° C. ¹ H NMR δ_(H) (200 MHz; CDCl₃) 0.8-1.8 (10 H, m) and2.22 (1 H, tt) (cyclohexyl); 2.31 (3 H, s, NMe); 2.6 (2 H, m) and 3.9 (2H, m (NCH₂ CH₂ N) 2.7 (2 H, m, NCH₂); 4.1-4.3 (3 H, m, OCH₂ CH); 6.7-6.9(4 H, m, benzodioxan); 7.2-7.3 (2 H, m pyridine H3 and H5); 7.74 (1 H,dt, pyridine H4); and 8.51 (1 H, dd, pyridine H6).

EXAMPLE 8N-(2-(N'-(7-(5,6,7,8-Tetrahydroquinolinyl))methylamino)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide (a)N-(2-Pyridinyl)-2-(N'-(7-(5,6,7,8-tetrahydroquinolinyl))methylamino)acetamide

A solution of N-methyl-5,6,7,8-tetrahydroquinoline-7-amine (7.08 g, 12.8mmol), N-(2-pyridyl) 2-chloroacetamide (2.19 g, 12.8 mmol) anddiisopropylethylamine (1.66 g, 12.8 mmol) in N,N-dimethylformamide (70ml) was stirred at room temperature overnight. The reaction mixture waspoured into water (200 ml) and washed with ethyl acetate (2×100 ml). Thecombined organic phases were washed with brine (100 ml), water (100 ml),dried (MgSO₄) and concentrated to afford an oil. The crude oil waschromatographed on alumina, gradient eluting with ethyl acetate:hexane(1:1) and ethyl acetate to give the title compound of step (a) as an oil(2.67 g).

(b)N-Methyl-N-(2-(2-pyridinylamino)ethyl(-5,6,7,8-tetrahydroquinoline-7-amine

A solution of the product of step (a) (1.70 g, 5.74 mmol) andborane-methyl sulphide complex in toluene (2.0 M, 8.60 ml, 17.2 mmol) intetrahydrofuran (15 ml) was heated under reflux for 3 h. Methanol (5 ml)was added dropwise to the cooled (0° C.) reaction mixture which wassubsequently concentrated under reduced pressure. The residue wasdissolved in a mixture of water (10 ml) and concentrated hydrochloricacid (10 ml). The solution was heated under reflux for 40 min, cooled(0° C.) and basified with aqueous sodium hydroxide (2 M). The basicsolution was washed with ethyl acetate (3×30 ml) and the combinedorganic phases washed with brine (30 ml), water (30 ml), dried (MgSO₄)and concentrated to give the title compound of step (b) as an oil (1.26g).

(c)N-(2-(N'-(7-(5,6,7,8-Tetrahydroquinolinyl))methylamino)ethyl-N-(2-pyridinyl)cyclohexanecarboxamide

A solution of the product of step (b) (1.26 g, 4.46 mmol),cyclohexanecarbonyl chloride (0.65 g, 4.46 mmol), diisopropylethylamine(0.58 g, 4.46 mmol) and a catalytic amount of4-N,N-dimethylaminopyfidine in dichloromethane (15 ml) was stirredovernight at room temperature. The separated organic phase was washedwith water (15 ml), dried (MgSO₄) and concentrated to afford an oil(1.28 g). The crude oil was chromatographed on alumina, gradient elutingwith ethyl acetate:hexane (5:4) and ethyl acetate to give an oil. Theoil was dissolved in ethyl acetate and acidified with ethereal hydrogenchloride to afford an off-white hygroseopic solid. The solid wasredissolved in isopropanol, concentrated and triturated with ethylacetate to afford the dihydrochloride salt of the title compound as ahygroscopic pale-yellow powder (0.25 g) mp=140°-145° C. ¹ H NMR δ_(H)(200 MHz; (CD₃)₂ SO) 0.8-1.8 (10 H, m) and 2.3 (1 H, m) (cyclohexyl);2.0 (1 H, m), 2.4 (1 H, m), 3.0-3.8 (4 H, m) and 3.9 (1 H, m)(tetrahydroquinoline); 2.85 (3 H, br. s, NMe); 3.0-3.8 (2 H, m) and 4.15(2 H, m) (NCH₂ CH₂ N); 7.45 (1 H, dd, pyridine H5); 7.63 (1 H, d,pyridine H3); 7.85 (1 H, dd, tetrahydroquinoline H3); 8.00 (1 H, dt,pyridine H4); 8.34 (1 H, d, tetrahydroquinoline H4); 8.63 (1 H, dd,pyridine H6); and 8.70 (1 H, d, tetrahydroquinoline H2).

We claim:
 1. A compound of the general formula ##STR15## or a pharmaceutically acceptable salt thereof whereinR¹ is pyridinyl, R² is C₃ -C₈ cycloalkyl, R³,R^(3') and R⁴ each represent hydrogen or C₁ -C₆ alkyl, R⁵ is ##STR16## R⁶ is hydrogen, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, hydroxy, halogen trifluoromethyl, C₁ -C₆ alkoxycarbonyl, carboxamido, nitro, cyano, amino, C₁ -C₆ alkylamino, di-C₁ -C₆ alkylamino or C₁ -C₆ alkylcarbonyl.
 2. A compound according to claim 1 wherein R¹ is 2-pyridinyl; and R² is cyclohexyl.
 3. A compound as claimed in claim 2 wherein R⁵ is a group of formula ##STR17## (where R⁶ is as defined in claim 1).
 4. A compound as claimed in claim 2 wherein R⁵ is a group of formula ##STR18##
 5. A compound as claimed in claim 2, wherein R⁵ is a group of formula ##STR19## (where R⁶ is as defined in claim 1).
 6. A compound as claimed in claim 2 wherein R⁵ is a group of formula ##STR20##
 7. A compound as claimed in claim 2 wherein R⁵ is a group of formula ##STR21## (where R⁶ is as defined in claim 1).
 8. A compound as claimed in claim 2 wherein R⁵ is a group of formula ##STR22##
 9. A compound as claimed in claim 2 which isN-(3-(N'-(1,2,3,4-tetrahydro-8-methoxynaphth-2-yl)methylamino)-2-propyl) N-(2-pyridinyl)cyclohexanecarboxamide or N-(3-(N'-(5,6,7,8-tetrahydroquinolin-7-yl)methylamino)-2-propyl)-N-(2-pyridinyl) cyclohexanecarboxamide or N-(3-(N'-(2-(3-(5-methoxyindolyl)ethyl))methylamino)-2-propyl)-N-(2-pyridinyl) cyclohexanecarboxamide or N-(3-(2-(2,3-dihydro-1,4-benzodioxinyl)methylamino)-2-propyl)-N-(2-pyridinyl) cyclohexanecarboxamide or N-(4-aza-6-hydroxy-7-(1-naphthyloxyl)-2-heptyl)-N-(2-pyridinyl) cyclohexanecarboxamide or N-(4-aza-6-(1-naphthyloxy)-4-propyl-2-hexyl)-N-(2-pyridinyl) cyclohexanecarboxamide or N-(2-(N'-(2-(2,3-dihydro-1,4-benzodioxinyl)methyl)methylamino)ethyl-N-(2-pyridinyl) cyclohexanecarboxamide or N-(2-(N'-(7-(5,6,7,8-tetrahydroquinolinyl))methylamino)ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide or a pharmaceutically acceptable acid addition salt thereof.
 10. A pharmaceutical composition for us as 5HT_(1A) antagonist comprising a compound claimed in claim 2 in association with a pharmaceutically acceptable carrier.
 11. A compound of claim 2 which is N-(3-(N'-(1,2,3,4-tetrahydro-8-methoxynaphth-2-yl) methylamino)-2-propyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.
 12. A compound of claim 2 which is N-(3-(N'-(5,6,7,8-tetrahydroquinolin-7-yl)methylamino) 2-propyl)-N-(2-pridinyl)cyclohexanecarboxamide or a pharamceutically acceptable salt thereof.
 13. A compound of claim 2 which is N-(3-(N'-(2-(3-(5-methoxyindolyl)ethyl))methylamino) 2-propyl)-N-(2-pyridinyl)cyclohexane-carboxamide or a pharmaceutically acceptable salt thereof.
 14. A compound of claim 2 which is N-(3-(2-(2,3-dihydro-1,4-benzodioxinyl)methylamino) 2-propyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.
 15. A compound of claim 2 which is N-(4-aza-6-hydroxy-7-(1-naphthyloxyl)-2-heptyl) N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.
 16. A compound of claim 2 which is N-(4-aza-6-(1-naphthyloxy)-4-propyl-2-hexyl) N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.
 17. A compound of claim 2 which is N-(2-(N'-(2-(2,3-dihydro-1,4-benzodioxinyl)methyl) methylamino)ethyl-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.
 18. A compound of claim 2 which is N-(2-(N'-(7-(5,6,7,8-tetrahydroquinolinyl))methylamino) ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof. 